I am a professor of cardiology, epidemiology, and public health at the Yale University School of Medicine and director of the Yale-New Haven Hospital Center for Outcomes Research and Evaluation I also serve on numerous cardiovascular care committees for national organizations, including the American Heart Association and the American College of Cardiology and am an elected member of the Association of American Physicians, the American Society for Clinical Investigation, and the Institute of Medicine. I've published more than 500 articles and am the author of the book, "The Expert Guide to Beating Heart Disease."

JAMA’s publication the NIH’s Trial to Assess Chelation Therapy (TACT) unleashed a spate of criticism directed at the investigators and their science. The trial showed that patients randomized to chelation therapy had a lower risk of a combined endpoint of death, heart attack, stroke, percutaneous coronary intervention, bypass surgery or hospitalization for angina than those who received a placebo infusion. I wrote in a Forbes blog that I found the results to be surprising and inconvenient – I did not think that the evidence was strong enough to make me recommend the therapy to others – I said that there is a need to replicate such surprising findings – but I noted that the results should not merely be dismissed – they deserved attention and merited discussion.

For many people, however, it was untenable to think that this therapy could have any positive effect and they focused attention on possible weaknesses in the study design and implementation (which is fair) – and on the credibility of the lead investigators (which I did not think was fair). I found the shrill and brutish nature of some of the comments about the trial and the investigators to be offensive. I know many of the lead authors of the study. These individuals together have extensive experience conducting large trials, are widely respected clinical scientists, had overcome considerable challenges in the implementation of the study, and had no stake in the outcome.

However, amid the cacophony, many individuals did raise good questions about the study. To try to steer the public dialogue back to the science – and to promote more civil discourse, I assembled the key questions being raised about the study and asked the authors to respond. Some of these questions may seem like inside baseline, but they are issues that have to do with whether the study can be trusted and how we should react to the results.

The entire interview is publicly available on CardioExchange, a NEJM online community that fosters dialogue among physicians interested in cardiovascular disease. Here are some highlights, slightly edited for brevity, that I wanted to share with readers of Forbes.

A major comment concerns the components of the chelation therapy, specifically about the inclusion of procaine and heparin and their possible effects on cardiovascular outcomes. Why were they included, and do you think they had an effect?

The NIH called for a definitive trial of EDTA chelation therapy, as it was currently being implemented in clinical practice. When we looked into the infusions, we found that they included many compounds, not just EDTA. Therefore, to achieve a result that would be consistent with how chelation therapy is actually used in practice, we chose to mimic precisely the most prevalent infusion in use. We have no reason to believe that a small amount of procaine or 2500 U of unfractionated heparin once weekly would affect outcomes to the extent that we found in TACT.

In his editorial, Steve Nissen complained that the sponsors had access to the results during the course of the study. Is this atypical for an NIH trial?

The TACT trial was conducted under a policy that allowed NIH staff to have access to unblinded data. At all times there was a firewall between trial decision makers who were blinded and NIH staff who were unblinded, to prevent the possibility of improper influence by unblinded staff. NIH staff members were unblinded primarily to assess safety issues with the intervention, not efficacy.

The goal of the Program Officers and other NIH personnel is to safeguard the integrity of the trial, not to sway the results either way. There is no indication of improper influence exerted by NIH program staff who saw unblinded data.

Some people have claimed that unblinding might have biased the trial. Is there evidence of unblinding?

All necessary precautions were taken to ensure blinding was preserved in the study. Both the placebo and active infusions were shipped in identical refrigerated containers. Neither EDTA nor ascorbic acid is stable if shipped mixed with the other 8 components of the chelation solution. Thus, the shipped and refrigerated pack contained one syringe with EDTA (or placebo), one syringe with ascorbic acid (or placebo), and a bag for intravenous infusion with all the other components already mixed (or normal saline only).

The ascorbic acid solution has a pale yellow color, which upon mixing becomes indistinguishable from the clear saline placebo solution. The syringes containing ascorbic acid or placebo were covered in translucent yellow adhesive tape, thereby blinding the pale yellow color of ascorbic acid. In addition, ascorbic acid, in the concentration provided by the manufacturer, is viscous. The placebo ascorbic acid solution contained enough 50% dextrose to mimic the viscosity of the active ascorbic acid solution.

In the end, science will advance through active and open discourse. Ideally, the dialogue is respectful and civil. People can disagree, but the discussion does not need to be acrimonious. The authors are setting a good example by their willingness to answer all the questions posed to them.

And interestingly, best I can tell, those who are so against the trial are actually in agreement with the assessment of the authors that the evidence is not yet strong enough to recommend the routine use of this therapy. Imagine that, agreement on the key issue – whether practice should change.

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